Increased levels of soluble TNF-alpha receptors and cellular adhesion molecules in patients undergoing bioincompatible hemodialysis

BACKGROUND: The study aimed to differentiate the effects of hemodialysis (HD) and chronic renal failure (CRF) on the levels of circulating tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha receptors p55 and p75, soluble vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), soluble endothelial-leukocyte adhesion molecule-1 (sE-selectin) and sP-selectin in 18 patients on regular HD treatment with cuprophane membrane in relation to 15 non-dialyzed CRF patients and 15 healthy controls. METHODS: The serum concentrations were determined with standard ELISA assays. RESULTS: Blood serum p75 and p55 were approximately tenfold increased in CRF (36.7 +/- 6.2 and 27.1 +/- 5.6 ng/ml) and HD patients (45.6 +/- 18.4 and 28.7 +/- 5.9 ng/ml) before the HD session (HD 0), during (HD 20) the session (45.7 +/- 18.4 and 28.5 +/- 7.3 ng/ml) and after (HD 240) the HD session (52.1 +/- 17.4 and 30.9 +/- 8.2 ng/ml) in comparison to control values (5.6 +/- 1.3 and 2.4 +/- 0.8 ng/ml, respectively) (p < 0.01). The highest increment of p75 at the end of HD session (HD 240) was also significantly higher than at preceding time points (HD 0 and 20) (p < 0.05). However, the remaining study parameters did not change during an HD session. Also, there were no relevant changes in TNF-alpha levels if (HD 0) 22.7 +/- 21.5 ng/ml and (HD 240) 21.1 +/- 18.9 ng/ml were compared. Chronic HD status was related to the increase of sVCAM-1 and sICAM-1 levels. Prior to HD, T0 sVCAM-1 and sICAM-1 concentrations were 2,180.4 +/- 761.8 and 567.3 +/- 218.8 ng/ml, during HD (T20): 2,172.7 +/- 759.2 and 602.3 +/- 379.9 ng/ml, and after HD (T240): 2,401.6 +/- 756.4 and 648.3 +/- 183.5 ng/ml, respectively (p < 0.05 vs. controls and CRF patients). sVCAM-1 and sICAM-1 serum levels (1,262.2 +/- 472.9 and 165.6 +/- 50.4 ng/ml) were similar in CRF patients and healthy controls (854.4 +/- 241.5 and 217.6 +/- 74.2 ng/ml, respectively). Even though serum sE- and sP-selectin in CRF patients did not differ from the control (39.8 +/- 21.3 vs. 42.1 +/- 18.9 ng/ml and 187.9 +/- 66.9 vs. 198.8 +/- 62.2 ng/ml, respectively), their levels were increased in HD patients up to 111.9 +/- 54.6 and 453.2 +/- 231.1 ng/ml in patients prior to HD, 118.7 +/- 66.2 and 350.8 +/- 114.8 ng/ml during the HD session and then 132.3 +/- 61.1 and 368.3 +/- 126.6 ng/ml, respectively, after its completion (p < 0.05 in comparison with CRF patients and controls). CONCLUSIONS: The increased circulating TNF-alpha receptors appear more associated with the uremic milieu than HD-related systemic inflammation, whereas increased soluble cellular adhesion molecules in patients undergoing bioincompatible HD may be related to the enhanced systemic inflammation specifically due to maintenance HD.     

Circulating soluble adhesion molecules in systemic vasculitis

The plasma levels of soluble intercellular adhesion molecule-1(sICAM-1), E-selectin (sE-selectin), and vascular cell adhesionmolecule-1 (sVCAM-1), might reflect endothelial activation andinjury and would therefore be useful markers of disease activityin vasculitis. To investigate this we measured the levels ofsICAM-1, sE-selectin, and sVCAM-1 by two-site ELISAs in theplasma of patients with (a) active vasculitis (n = 16), (b)vasculitis in remission (n = 15), (c) chronic renal failure(CRF) (n = 10), and (d) normal healthy controls (n = 10). PlasmasICAM-1 levels were significantly higher in patients with activevasculitis, 323 ng/ml (193–607) compared with patientswith inactive vasculitis, 199 ng/ml (131–297); P = 0.0006and healthy controls, 188 ng/ml (138–259); P =0.0002.Plasma sE-selectin levels were also significantly higher inthe patients with active vasculitis, 45 ng/ml (15–65)compared with patients with inactive vasculitis, 25 ng7sol;ml(15–55); P=0.027 but not when compared with healthy controls,35 ng/ml (20–55); P=0.16. There was no difference in plasmasVCAM-1 levels between patients with active vasculitis, OD 0.56(0.45–0.85) and inactive disease, OD 0.58 (0.47–0.79)(P=0.12) or with healthy controls OD 0.49 (0.42–0.68)(P=0.48). There were no significant differences between theplasma levels of any of the soluble adhe sion molecules betweenpatients with active vasculitis and patients with chronic failure.In patients with a vasculitis there was a significant correlationbetween sICAM-1 and plasma C-reactive protein (CRP) (r=0.60,P=<0.01) and plasma von Willebrand factor (vWF) (r=0.42,P<0.05). Likewise there was a cor relation between sE-selectinand CRP (r=0.45, P<0.02) but not with vWF. There was a significantcorrelation between sICAM-1 and sE-selectin (r=0.38, P<0.05),but not between sICAM-1 and sVCAM-1 or sE- selectin and sVCAM-1.No correlation was found between sVCAM-1 levels and CRP andvWF concentrations or between the levels of any of the solubleadhesion molecules and serum creatinine. Plasma levels of sICAM-iand of sE-selectin but not of sVCAM-1 reflect disease activityin vasculitis and may be markers of endothelial and or tissueinjury in these disorders.     

Elevated serum levels of soluble adhesion molecules predict death in pre-dialysis patients: association with malnutrition, inflammation, and cardiovascular disease.

BACKGROUND: Atherosclerotic cardiovascular disease, malnutrition, and increased levels of pro-inflammatory cytokines are common features in patients with chronic renal failure, and contribute to the high mortality rate observed in these patients. A diverse group of soluble cellular adhesion molecules (CAM) (sVCAM-1, sICAM-1 and sE-selectin) are expressed on the surface of vascular endothelial cells in response to pro-inflammatory cytokines and may play an important role in the atherogenic process. METHODS: Serum levels of sVCAM-1, sICAM-1 (n=87) and sE-selectin (n=71) were analysed in a cohort of 88 patients (50+/-1 years) with chronic renal failure. The presence of malnutrition (subjective global assessment (SGA) and serum albumin), inflammation (C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-alpha), and serum hyaluronan), and cardiovascular disease (CVD) were assessed at a time-point close to the start of dialysis treatment (GFR 7+/-1 ml/min). Blood lipid parameters were also assessed. RESULTS: Significant correlations were observed between Log high-sensitivity CRP (hsCRP) and sVCAM-1 (R=0.39; P<0.01) and sICAM-1 (R=0.47; P:<0.001) levels but not between Log hsCRP and sE-selectin levels in 60 patients examined with a hsCRP assay. Also serum concentrations of Log hyaluronan correlated significantly to sVCAM-1 (R=0.34; P<0.01) and sICAM-1 (R=0.29; P<0.05) levels. Malnourished patients (SGA>1) had elevated serum concentrations of sVCAM-1 (1436+/-94 vs. 1105+/-53 ng/ml; P<0.01) compared to well-nourished patients (SGA 1). Patients with clinical signs of CVD (n=26) had elevated serum levels of sICAM-1 (282+/-18 vs. 242+/-9 ng/ml; P<0.05) compared to 61 patients without signs of CVD. Plasma Log lipoprotein (a) (Lp(a)) levels correlated significantly with sVCAM-1 (R=0.30; P<0.01). Survival analysis by the Cox regression model showed that elevated sICAM-1 was, independent of age, SGA, CVD, and Log CRP, significantly related to an increased mortality rate. CONCLUSIONS: Elevated serum concentrations of soluble adhesion molecules are found in pre-dialysis patients who are malnourished, inflamed, and have signs of cardiovascular disease. These data also suggest that sICAM-1 is an independent predictor of mortality in pre-dialysis patients. Further studies are needed to determine if inflammation causes accelerated atherogenesis via effects on soluble adhesion molecules or if elevated serum levels of soluble adhesion molecules are merely markers of endothelial activation in patients with chronic renal failure.     

Hemodialysis procedure does not affect the levels of sICAM-1 and sVCAM-1 in patients with end stage renal disease

Atherosclerosis is by far the leading cause of mortality and morbidity in patients with end stage renal disease undergoing chronic hemodialysis (HD). Vascular endothelial cell adhesion molecules like the intercellular adhesion molecule-1 (ICAM-1) and the vascular cell adhesion molecule-1 (VCAM-1) are involved in the pathogenesis of atherosclerosis. Their soluble forms (sICAM-1, sVCAM-1) are considered potential serum markers of endothelial activation and atherosclerosis. The aim of this study was to clarify the influence of the HD procedure on the levels of sICAM-1 and sVCAM-1 in patients with end stage renal disease. We evaluated 35 clinically stable patients (18 males, 17 females, mean age 61 +/- 12) on chronic HD treatment. Diabetes mellitus coexisted in eight patients and arterial hypertension in 23 patients. Blood was drawn before, every hour during, and after a single HD session in each patient. Low-flux cuprophane dialyzers (GFS 12, Gambro, Lund, Sweden) were used in 22 and high-flux polysulfone dialyzers (Hemoflow F 60S, Fresenius, Oberursel, Germany) in 13 cases. At 30 min into the HD session (n=31, 20 low-flux HD, 11 high-flux HD) blood was drawn simultaneously from the entrance and the exit line of the dialyzer. From all these samples, serum concentrations of sICAM-1 and sVCAM-1 were determined by commercially available enzyme immunoassays (ELISA, R&D Systems, Minneapolis, USA). Results were corrected according to hemoconcentration, where appropriate. Plasma levels of sVCAM-1 were elevated in patients with end stage renal disease before the beginning of the dialysis session when compared to healthy controls (1449 +/- 497 ng/mL vs. 691 +/- 118 ng/mL). On the contrary, such an elevation was not found in the case of sICAM-1 (231 +/- 58.5 ng/mL vs. 236.4 +/- 96.8 ng/mL in healthy controls). These levels remained stable in all measurements throughout the dialysis procedure. Furthermore, serum sICAM-1 and sVCAM-1 levels remained unaltered after the passage of the dialyzer. The levels of sICAM-1 and sVCAM-1 were not influenced by the existence of diabetes mellitus, hypertension, or by the utilization of biocompatible, high flux dialyzers. Our study confirms that in chronic HD patients serum levels for sVCAM-1 are elevated. The levels of adhesion molecules are not affected by the HD procedure. These findings probably can be attributed to a decreased renal clearance or catabolism of sICAM-1 and sVCAM-1 and to the different sources of the two molecules. Neither coexisting diabetes mellitus nor arterial hypertension influences the circulating levels of these adhesion molecules. The functional role of sVCAM-1 and sICAM-1, the exact renal contribution to their metabolism, and their role as markers of atherosclerosis in chronic renal disease need further evaluation.     

Serum VCAM-1, ICAM-1, and L-selectin levels in children and young adults with chronic renal failure

Children and young adults with chronic renal failure (CRF) present with an impaired immune response. Our aim was to analyze whether leukocyte migration, determined by adhesion molecules, is disturbed in the course of CRF, hemodialysis (HD), and peritoneal dialysis (PD). Soluble (s) VCAM-1, ICAM-1, and L-selectin serum levels were evaluated by ELISA in 15 patients with CRF, 22 patients on cuprophane membrane HD, 24 patients on PD, and in 15 controls. The sVCAM-1 levels in all groups were significantly elevated compared with controls. The levels in HD patients were higher than in CRF patients (P <0.05), while levels in PD patients were higher than in CRF and HD (P <0.001 and P <0.01, respectively). The sICAM-1 concentrations in CRF and PD patients were significantly elevated compared with controls (P <0.001 and P <0.0001, respectively); in PD patients sICAM-1 levels were higher than in HD patients (P <0.001), but there were no differences between other groups. sL-selectin levels were decreased in all groups compared with controls. The levels in HD patients were the lowest and the differences, compared with CRF and PD patients, were significant (P <0.05 and P <0.01, respectively). Children and young adults with CRF and on maintenance dialysis have altered concentrations of soluble adhesion molecules, resulting from either inadequate clearance or disturbed synthesis and release. The differences in sVCAM-1 levels between CRF and both groups of patients on dialysis, as well as the differences in sL-selectin concentrations between HD and CRF patients, indicate that these disturbances are aggravated by maintenance dialysis, particularly HD.     

Soluble adhesion molecules in children and young adults on chronic hemodialysis

Children on chronic hemodialysis (HD) present with impaired immunity that may result from disturbances in leukocyte migration, caused by changes in expression of adhesion molecules on endothelium and immunocompetent cells. However, it is still not clear whether the type of dialyzer or a single dialysis session influences the concentrations of soluble adhesion molecules in these patients. We evaluated by ELISA serum levels of soluble (s) VCAM-1, ICAM-1, L-selectin, and P-selectin in 22 patients on cuprophane HD (CU), 8 on polysulfone HD (PS), 10 on vitamin E-modified cellulose HD (VE), and 15 controls. In all HD patients, sVCAM-1 levels were elevated compared with controls and were higher in CU than in VE. The sICAM-1 concentrations were increased in VE compared with controls, but remained unchanged in CU and PS. The sL-selectin levels were reduced in all HD patients. The mean values of sP-selectin were comparable in CU, PS, and controls. The lowest levels were observed in VE. In CU patients, sVCAM-1, sICAM-1, and sP-selectin concentrations rose after HD. A single PS session had no impact on adhesion molecules, whereas a VE session increased the level of sVCAM-1. The type of dialysis membrane may change the profile of adhesion molecule concentrations, thus influencing the immune system of a child on HD. The increase in levels of adhesion molecules in the course of a single HD session, which was pronounced in CU and VE patients, suggests poor biocompatibility of these dialyzers.     

Soluble adhesion molecules in end-stage renal disease: a predictor of outcome.

BACKGROUND: Inflammation is thought to contribute to initiation and aggravation of atherosclerosis through a process predominantly mediated by adhesion molecules. The aims of this study were to investigate the association between the concentrations of circulating soluble intercellular (sICAM-1) and vascular cellular (sVCAM-1) adhesion molecules and clinical outcome, and to evaluate the effect of antihypertensive drugs on sICAM-1 and sVCAM-1 concentrations in end-stage renal disease (ESRD) patients. METHODS: We prospectively investigated 310 (191 males) incident ESRD patients, 53+/-12 years old, shortly before the start of renal replacement therapy. Glomerular filtration rate (GFR) was 6.4 (range 0.8-16.5) ml/min/1.73 m(2). Plasma sICAM-1 and sVCAM-1 were measured by enzyme-linked immunosorbent assay (ELISA) kits. Survival was determined from the day of examination, with a mean follow-up period of 39 (range 1-123) months. RESULTS: In non-adjusted analysis, high sICAM-1 and sVCAM-1 levels were associated with all-cause and cardiovascular (P<0.001) mortality. After adjusting for age, gender, diabetes mellitus, serum cholesterol, C-reactive protein (CRP), subjective global assessment and angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB), the association between high sICAM-1 and mortality remained significant for all-cause (HR 1.9; CI 1.2-2.9, P = 0.004) and cardiovascular (HR 1.8; CI 1.1-3.1, P = 0.02) mortality, and a high sVCAM-1 was associated with all-cause mortality (HR 1.7; CI 1.04-2.7, P = 0.03). Furthermore, the concentration of sICAM-1, but not sVCAM-1, was lower in patients receiving ACEI/ARB (254+/-83 vs 275+/-92 ng/ml; P<0.05) or patients receiving calcium channel blockers (CCB, 251+/-75 vs 273+/-95 ng/ml; P<0.05) than in non-users. CONCLUSIONS: In ESRD patients, sICAM-1 and sVCAM-1 are independent predictors of all cause and cardiovascular death. The use of ACEI/ARB or CCB was associated with decreased concentrations of soluble adhesion molecules.     

Value of circulating adhesion molecules in assessing cardiac allograft vasculopathy.

Circulating adhesion molecules have been implicated in the development of spontaneous and transplant coronary artery disease. We analyzed soluble (s) intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1 (sVCAM-1), and sE-selectin levels from the coronary sinuses of 25 cardiac allograft recipients, and we correlated these molecules with the degree of acute rejection detected in endomyocardial biopsy specimens and the presence of transplant vasculopathy assessed with coronary angiography. We found that sVCAM-1 significantly increased in patients with transplant vasculopathy compared with those without transplant vasculopathy, whereas sE-selectin and sICAM-1 did not. Therefore, increased coronary sinus levels of sVCAM-1 is a reliable marker in assessing cardiac transplant vasculopathy.     

Effect of pravastatin on markers of endothelial activation in dialysis patients

AIM: The aim of this pilot study was to test the effect of pravastatin on serum levels of high-sensitivity CRP (hs-CRP), IL-6 and the soluble adhesion molecules sVCAM-1, sICAM-1 and sE-selectin in chronic dialysis patients. METHODS: At the commencement of the study, serum levels of lipids, liver function tests and endothelial markers (CRP, IL-6, sICAM-1, sVCAM-1, sE-selectin) were measured. Patients then commenced 1 month of 10 mg of pravastatin per day, and if tolerated, then 4 months of 40 mg of pravastatin per day. Serum levels of lipids, liver function tests and endothelial markers were repeated after the total of 5 months of pravastatin therapy. RESULTS: Thirty-nine patients were enrolled, and 25 (male/female 17/8; 21 haemodialysis, 4 peritoneal dialysis) patients completed the study. Pravastatin therapy significantly improved the patients' lipid profiles, but had no significant effect on the levels of CRP, IL-6, sICAM-1, sVCAM-1, or sE-selectin. CONCLUSION: Short-term (5 months) treatment with pravastatin in patients receiving chronic dialysis improved their lipid profile, but had no significant effect on surrogate markers of endothelial activation.     

Soluble adhesion molecule profiling in preoperative infants with biliary atresia

Objective

Intercellular adhesion molecule (ICAM) expression in liver and bile duct remnant is a feature of the inflammatory component of biliary atresia (BA). Circulating levels of such soluble adhesion molecules (SAM) should reflect intrahepatic disease and would prove a useful adjunct in the evaluation of BA.

Study Design

Serum ICAM-1 (sICAM-1), serum vascular cell adhesion molecule (sVCAM-1), and serum E selectin (sE-selectin) were measured by enzyme-linked immunosorbent assay in infants with BA at the time of portoenterostomy and stratified by outcome. Results are quoted as medians (range). Binary logistic regression analysis and actuarial survival curves were used to investigate the relationship of SAM profile to outcome. Significance was assumed at P values of ≤.05.

Results

Sixty-one infants with BA were treated between 1996 and 2002 and at follow-up; 39 of these were alive and jaundice-free (good outcome, n = 39); 21 had been transplanted, and 1 died (poor outcome, n = 22). Preoperative values for sICAM-1 were 1233 (400-2000) ng/mL; sVCAM-1, 1204 (517-1921) ng/mL; and sE-selectin, 71 (26-192) ng/mL. sVCAM-1 (P < .0001) and sICAM-1 (P < .0001) significantly increased compared with normal control infants, although sE-selectin did not (P = .17). There was a significant correlation of age at surgery with sICAM-1 (r = 0.33, P = .01) but not with sVCAM-1 (r = 0.16, P = .23) or sE-selectin (r = 0.05, P = .70).Binary logistic regression analysis showed that the variables, sICAM-1, sE-selectin, or age at surgery, were not significant predictors of outcome, although sVCAM-1 approached significance (P = .069). A cutoff value for sVCAM-1 of 1380 ng/mL was defined by receiver operating characteristic curve analysis, and the cohort of patients with sVCAM-1 (>1380 ng/mL) showed a significantly worse actuarial survival (P = .05).

Conclusion

Levels of sICAM-1 and sVCAM-1 are grossly elevated in BA, whereas sE-selectin levels are normal. Only sVCAM-1 levels have prognostic significance. SAM profiling has the potential to monitor the inflammatory process of BA and may guide more novel forms of pharmacological intervention or immunomodulation.     

S-100b, sE-selectin, and sP-selectin for Evaluation of Hypoxic Brain Damage in Patients after Cardiopulmonary Resuscitation: Pilot Study

S-100b is thought to be a screening marker of hypoxic brain damage in patients with cardiac arrest. However, the time-dependent occurrence and relevance of increased S-100b serum levels in out-of-hospital patients with cardiopulmonary resuscitation (CPR) is still discussed. The purpose of our study was to evaluate the diagnostic utility of S-100b measurements in comparison to that of adhesion molecules sE-selectin and sP-selectin in patients with CPR. Sixteen out-of-hospital patients (median age 69.6 years; range 59.2–82.2 years) suffering from cardiac arrest due to ventricular fibrillation, asystole, or electromechanical dissociation were recruited prospectively. Blood samples were drawn on scene after the return of spontaneous circulation (ROSC) and 12 hours after successful CPR. The reference group consisted of 10 patients with isolated severe head trauma (SHT) (Glasgow Coma Score ≤ 8), and the control group comprised 20 healthy volunteers. Serum concentrations of S-100b, determined by immunoluminometric assay, were compared with serum levels of sE-selectin and sP-selectin measured by an enzyme-linked immunosorbent assay and correlated with the patients' survival. In the CPR group, S-100b serum levels (2.37 ng/ml; 1.37–4.09 ng/ml) at study entry (11.6 minutes after arriving on scene) did not significantly differ from those of SHT patients (2.88 ng/ml; 1.78–8.81 ng/ml). Both groups showed significant differences from the healthy controls (0.04 ng/ml; 0.01–0.82 ng/ml). At 12 hours after CPR the serum levels had decreased to 0.41 ng/ml (0.24–0.51 ng/ml) but continued to be significantly elevated compared to that of the control group. sE-selectin values in serum increased from 56.00 ng/ml (38.50–85.50 ng/ml) on scene to 79.00 ng/ml (52.00–127.00 ng/ml) after 12 hours (p < 0.05). The first measurements differed significantly from serum levels of the control group (22.50 ng/ml; 14.00–34.00 ng/ml) and from those of the SHT group (45.00 ng/ml; 39.00–63.75 ng/ml). At 12 hours after study entry the sE-selectin values were not significantly different from those of the SHT group (51.50 ng/ml; 39.00–95.88 ng/ml). sP-selectin serum levels increased slightly from 199.50 ng/ml (184.25–227.25 ng/ml) to 247.00 ng/ml (206.50–354.75 ng/ml). First and second measurements did not reveal any significant differences in either the SHT group or the healthy controls. When correlated with survival, S-100b measurements exhibited constantly high serum levels for patients, decreasing within the first 24 hours, whereas they decreased significantly in patients with longer survival. sP-selectin values on scene slightly increased in cases of survivals less than 24 hours after CPR. sE-selectin serum levels always remained within normal levels and revealed no significance later on. In contrast to the endothelium-derived adhesion molecules sE-selectin and sP-selectin, comparison of measurements of specific neuroprotein S-100b early after cardiac arrest and 12 hours later seem to provide an indication of the severity of hypoxic brain damage and the prognosis after CPR. Further investigations are required to better understand the CPR-related mechanisms of blood-brain barrier damage.     

Serum concentration of adhesion molecules in postoperative biliary atresia patients: relationship to disease activity and cirrhosis

BACKGROUND/PURPOSE: Biliary atresia (BA) is associated with progressive liver fibrosis, which may be mediated by immunologic abnormalities involving adhesion molecules. This study investigates the relationship between serum intercellular adhesion molecule-1 (sICAM-1), serum vascular cell adhesion molecule-1 (sVCAM-1), and the clinical and histologic severity of BA. METHODS: Serum ICAM-1 and VCAM-1 levels were measured by enzyme-linked immunosorbent assay in 35 patients with BA and 20 healthy controls. Standard liver function tests (LFTs), and frozen section liver biopsy specimens were used to determine liver status. On the basis of LFT results, the BA patients were classified into group I (n = 10; normal LFTs), group II (n = 15; elevated LFTs, anicteric), and group III (n = 10; elevated LFTs, icteric). Eight subjects in group II, and all subjects in group III had portal hypertension (PH). RESULTS: sICAM-1 levels were significantly elevated in group III (1760.0 +/- 717.5 ng/mL) compared with group II (555.1 +/- 199.4 ng/mL), group I (272.1 +/- 59.9 ng/mL) and controls (256.3 +/- 71.6 ng/mL). Although sVCAM-1 levels were significantly elevated in group III (1932.9 +/- 282.6 ng/mL) compared with group II (1054.3 +/- 297.0 ng/mL), group I (605.4 +/- 112.4 ng/mL), and controls (616.0 +/- 112.0 ng/mL; P <.001), there was no statistically significant difference between groups I, II, or controls. sVCAM-1 levels were elevated significantly in BA subjects in group II with PH (1253.0 +/- 245.1 ng/mL) compared with those who did not have PH (827.3 +/- 151.7 ng/mL; P <.01). PH did not affect sICAM-1 levels. There was strong expression of ICAM-1 and VCAM-1 in proliferating bile ductules, endothelial cells, and liver cells in group III compared with group II and controls. CONCLUSIONS: In BA, sICAM-1 and sVCAM-1 levels could be useful as markers of end-stage liver disease, with sVCAM-1 being more specific for PH. Induction of ICAM-1 and VCAM-1 may be an important factor in the development of cirrhosis.     

Soluble Adhesion Molecules and Myocardial Injury during Coronary Artery Bypass Grafting

Abstract Cardiopulmonary bypass is acknowledged to be one of the major causes of a complex systemic inflammatory response after cardiac surgery. Leukocyte-endothelial binding followed by neutrophil migration appears to play a central role. These interactions are mediated by adhesion molecules on the surface of activated cells. The present study compared the perioperative levels of soluble adhesion molecules after coronary artery bypass grafting (CABG) in patients with or without cardiopulmonary bypass (CPB). Altogether, 9 patients underwent off-pump revascularization and 11 did so with CPB. Plasma levels of soluble adhesion molecules sE-selectin and sP-selectin and soluble intercellular adhesion molecule-1 (sICAM-1) were measured before anesthesia induction and 1, 4, and 20 hours after reperfusion to the myocardium. The baseline plasma levels of the adhesion molecules were similar in the two groups. Perioperative levels of sE-selectin remained the same and did not differ between groups. Plasma sP-selectin increased in both groups, the change being significantly greater in the CPB group than that in the off-pump group (p = 0.001). Plasma sICAM-1 decreased during an early stage after CABG with CPB, recovering at 4 hours after reperfusion; and a significant increase in ICAM-1 was observed 20 hours later. In the off-pump group, sICAM-1 levels did not change at 1 and 4 hours after reperfusion but increased 20 hours later. Postoperative creatine kinase–muscle bound (CK-MB) levels were significantly higher in the CPB group than in the off-pump group (p = 0.001). The change in sP-selectin levels also showed a correlation with CK-MB values (r = 0.676, p = 0.001). The results indicated that off-pump revascularization is associated with reduced endothelial activation and myocardial injury.     

Circulating levels of soluble adhesion molecules in patients with ANCA-associated vasculitis

BACKGROUND: During inflammation, activated vascular endothelial cells and other cell types express various adhesion molecules, which facilitate the binding of circulating leukocytes and their extravasation in surrounding tissue (i.e. renal tissue). The serum concentration of circulating soluble adhesion molecules is supposed to reflect the degree of this activation. OBJECTIVE: In the first part of the study, we determined if the serum levels of the soluble intercellular adhesion molecule (sICAM)-1 and the soluble endothelial cell-leukocyte adhesion molecule (sELAM)-1, in patients affected by microscopic polyangiitis (MPA), associated with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibodies (ANCA), were related to the active and the inactive vasculitis phase. In the second part of the study, we examined the changes in circulating sICAM-1 and sELAM-1 levels and the clinical outcome of renal function in these patients. METHODS: We examined 20 MPO-ANCA-positive MPA patients in an acute phase and in a remission phase, after 6 months of treatment, and 50 subjects as controls, 30 with autosomal dominant polycystic kidney disease (ADPKD) in stable chronic renal failure (CRF) and 20 healthy volunteers (HS) with normal renal function. RESULTS: Regarding serum creatinine (Cr) concentration, no significant differences were found comparing active and inactive phases in the MPA group and the CRF group. Mean serum adhesion molecule levels in the MPA group were higher in the active phase compared to the inactive phase and to the CRF and HS groups. In addition, considering the outcome of serum Cr concentrations in the MPA group, the serum adhesion molecule levels were higher and decreased more slowly in patients with final high serum Cr concentrations than in patients with final normal serum Cr concentrations. CONCLUSION: Our data suggest that in MPO-ANCA-positive MPA patients, higher sICAM-1 and sELAM-1 levels during the active phase and their slower decline during the treatment period, could be a prognostic risk factor for CRF development.     

Markers for endothelial activation during open heart surgery

BACKGROUND: Reliable markers for endothelial activation are needed when studying biocompatibility of cardiopulmonary bypass. METHODS: Blood samples from 21 patients undergoing combined valve and coronary artery bypass surgery were collected before anesthesia (T1), after re-transfusion of blood from the heart-lung machine (T2), and on the first postoperative morning (T3). Concentrations of soluble markers were determined using sandwich enzyme-linked immunoadsorbent assay for sICAM-1, sVCAM-1, and sE-selectin. The sera were also used to stimulate human umbilical vein endothelial cells (HUVEC) in culture for 6 hours, in which activation was measured using cell enzyme immunoassay for mICAM-1 and mVCAM-1. RESULTS: The concentrations of sICAM-1 and sVCAM-1 increased during both measurement intervals (p < 0.05). The sICAM-1 T1 was 311.0 ng/mL (range, 271.0 to 350.7 ng/mL); the sICAM-1 T2 was 341.6 ng/mL (range, 322.0 to 422.0 ng/mL), and the sICAM-1 T3 was 400.2 ng/mL (range, 348.0 to 556.4 ng/mL; the sVCAM-1 T1 was 607.5 ng/mL (range, 497.8 to 813.8 ng/mL), the sVCAM-1 T2 was 755.3 ng/mL (range, 660.6 to 834.4 ng/mL), and the sVCAM-1 T3 was 1149.0 ng/mL (946.0 to 1406.0 ng/mL); whereas the sE-selectin increased from T1 to T3 (p < 0.01). Both the mICAM-1 (p < 0.002) and the mVCAM-1 (p < 0.005) increased on the human umbilical vein endothelial cells in culture after stimulation with the patient sera. The amounts of soluble markers in vivo were not correlated with the degree of endothelial activation in vitro, but were correlated with various operative variables including age, medication, and time of aortic cross-clamping. CONCLUSIONS: Endothelial cells were activated during cardiopulmonary bypass. The soluble adhesion molecules sICAM-1, sVCAM-1, and sE-selectin displayed different kinetics, rendering it difficult to determine a simple expression for the degree of endothelial cell activation. Clinically, sVCAM-1 seemed to be the best-suited marker for endothelial cell activation, because it was only associated with aortic cross-clamping and heparin and protamine doses, and it also showed the largest numerical changes.     

Soluble circulating cell adhesion molecules in haemolytic uraemic syndrome

Plasma concentrations of soluble vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin) and intercellular adhesion molecule-1 (sICAM-1) were measured by enzyme-linked immunosorbent assay in four groups of children. Group 1 consisted of 20 patients with acute diarrhoea-associated haemolytic uraemic syndrome (D+HUS), the aetiology of HUS being verocytotoxin-producingEscherichia coli infection in each case. Controls consisted of 11 patients who had previously had D+HUS (group 2), 12 with chronic renal failure (group 3) and 8 healthy controls (group 4). When compared with healthy controls, the acute D+HUS group had higher sVCAM-1 (median 1,875 ng/ml, range 1,200–6,450 ng/ml vs. 1,200 ng/ml, range 975–2,125 ng/ml), von Willebrand factor antigen, (1.9 U/ml, range 0.85–5.1 U/ml vs. 0.55 U/ml, range 0.3–1.57 U/ml), white cell count (WBC, 14.5×10⁹/l, range 7.8–43.1 10⁹/l vs. 8.9 10⁹/l, range 5.7–10.8 10⁹/l) and neutrophil count (PMN, 10.1×10⁹/l, range 4.3–26.5 10⁹/l vs. 4.3 10⁹/l, range 3.7–6.6 10⁹/l), allP<0.005, and sICAM-1 was reduced (230 ng/ml, range 130–340 ng/ml vs. 400 ng/ml, range 260–690 ng/ml),P<0.05. Within the acute D+HUS group there was a significant correlation between sICAM-1 and PMN (r=0.56,P<0.01). There was no correlation between any adhesion molecule and plasma creatinine or von Willebrand factor. Comparing the acute HUS group with children with chronic renal failure, WBC (P<0.001), PMN (P<0.01) and sVCAM-1 (P<0.01) were significantly elevated, but there was no difference between the von Willebrand factor (P=0.08) or the sICAM-1 (P>0.1). sVCAM-1 is elevated and sICAM-1 decreased in acute D+HUS. This pattern of altered adhesion molecule concentration is unlike that in adults with vasculitis and suggests that different endothelial regulatory factors are at play.     

Cytokines and adhesion molecules in renal vasculitis and lupus nephritis

Background: Plasma levels of some pro-inflammatory cytokines and soluble adhesion molecules have been suggested to be useful parameters to assess the activity of antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis and lupus nephritis. We hypothesized that the renal activity of these diseases is better reflected by the urinary excretion and fractional excretion of these molecules. Methods: Plasma levels and urinary excretion of tumour necrosis factor-&agr; (TNF-&agr;), interleukin (IL)-6, IL-8, and the soluble cell adhesion molecules sICAM-1 and sVCAM-1 were measured by enzyme-linked immunosorbent assay (ELISA) in 15 patients with ANCA-positive renal vasculitis (eight active, ANCA-A; six in remission, ANCA-R), six patients with active lupus nephritis (LN), 15 patients with IgA nephropathy (IgAN) and nine healthy subjects. Fractional excretion of selected cytokines and adhesion molecules was also calculated. Results: Patients with ANCA-A had increased urinary excretion and fractional excretion of TNF-&agr; (9.27±3.19% vs 0.58±0.02%, P<0.01), IL-6 (120.79±65.83% vs 1.89±0.34%, P<0.01) and increased fractional excretion of IL-8 (23.34±6.38% vs 2.56±1.07%, P<0.01) and sVCAM-1 (0.81±0.33% vs 0.03±0.02%, P<0.01) compared with controls. Urinary excretion of TNF-&agr; and IL-6 and fractional excretion of TNF-&agr;, IL-6 and IL-8 were higher in ANCA-A than in ANCA-R. Patients with LN had increased plasma TNF-&agr; (20.52±2.01 pg/ml vs 12.33±0.23 pg/ml, P<0.05) and sVCAM-1 (1537.88±276.36 ng/ml vs 692.26±44.42 ng/ml, P<0.05) and increased urinary excretion of TNF-&agr; (2.81±0.51 &mgr;g/mol creat vs 0.98±0.05 &mgr;g/mol creat, P<0.01), IL-8 (35.78±14.03 &mgr;g/mol creat vs 12.46±5.19 &mgr;g/mol creat, P<0.05) and sVCAM-1 (48.98±20.20 &mgr;g/mol creat vs 2.92±1.35 &mgr;g/mol creat, P<0.01) compared with controls. Patients with IgAN had, in comparison with controls only increased plasma TNF-&agr; (18.10±0.57 pg/ml vs 12.33±0.23 pg/ml, P<0.05). Conclusions: Urinary excretion and fractional excretion, but not plasma levels of selected proinflammatory cytokines (TNF-&agr;, IL-6 and IL-8) were increased in patients with active ANCA-positive renal vasculitis, but not in ANCA positive vasculitis in remission. These parameters may be useful to monitor the activity of this disease.     

Systemic and vascular inflammation is elevated in early IgA and type 1 diabetic nephropathies and relates to vascular disease risk factors and renal function.

BACKGROUND: Inflammation is implicated in cardiovascular disease (CVD) and mortality in end-stage renal failure (ESRF). Its importance in early renal disease is yet to be defined. METHODS: Serum levels of systemic and vascular inflammatory markers in early IgA nephropathy (IgAN) and control subjects were measured and related to renal function and vascular risk factors. A parallel study in type 1 diabetes mellitus subjects with (T1DM Nx) and without nephropathy (T1DM No Nx) was performed. RESULTS: Fifty-one IgAN patients aged 46+/-2 years (mean+/-SEM), calculated creatinine clearance (CrCl) 88+/-5 ml/min, were compared with 51 matched control subjects. Forty-six T1DM Nx patients aged 40+/-2 years, CrCl 84+/-5 ml/min, and 73 T1DM No Nx patients aged 38+/-2 years were also compared. High sensitivity C-reactive protein (hsCRP) was elevated in IgAN, T1DM Nx and T1DM No Nx patients compared with controls [4.2+/-0.6 (P < 0.001), 4.1+/-0.6 (P < 0.001), 2.6+/-0.4 (P < 0.05) vs 1.6+/-0.3 mg/l]. Levels in T1DM Nx patients were higher than in T1DM No Nx patients (P < 0.05). Inflammation and vascular dysfunction as measured by pulse pressure (PP) were related. HsCRP correlated with PP in IgAN and T1DM Nx (r = 0.47, P = 0.001; r = 0.40, P < 0.05). PP was the strongest independent predictor of hsCRP in IgAN (T = 2.45, P < 0.001), while body mass index (T = 7.83, P < 0.001) was the strongest predictor in T1DM Nx. Endothelial cell adhesion molecules were increased in T1DM Nx > IgAN > T1DM No Nx vs controls: soluble vascular adhesion molecule-1 (sVCAM-1) 760+/-30 (P < 0.001) > 663+/-34 (P = 0.001) > 601+/-21 (P < 0.05) vs 536+/-15 ng/ml; soluble intracellular adhesion molecule-1 (sICAM-1) 320+/-8 (P < 0.001) > 313+/-13 (P < 0.001) > 307+/-8 (P < 0.001) vs 244+/-6 ng/ml. sVCAM-1 levels were higher in T1DM Nx than in T1DM No Nx, P < 0.001. In IgAN and T1DM Nx, hsCRP correlated with sICAM-1 (r = 0.33, P = 0.017; r = 0.37; P = 0.017). sVCAM-1 was related to renal function in IgAN and T1DM Nx: serum cystatin C (r = 0.63, P < 0.001: r = 0.425, P = 0.002), and urine protein:creatinine ratio in IgAN (r = 0.48; P = 0.001). CONCLUSIONS: Systemic and vascular markers of inflammation are increased in early renal disease and relate to renal dysfunction and cardiovascular risk factors. Inflammation may be a common process in various renal diseases and may link and accelerate renal dysfunction and CVD.     

Soluble adhesion molecules in coronary surgery and cardiopulmonary bypass with pump prime aprotinin

OBJECTIVE: The purpose of the present study was to establish whether pump prime aprotinin could influence soluble adhesion molecules in patients undergoing elective coronary artery bypass surgery. DESIGN: Thirty patients admitted for first-time elective coronary artery bypass surgery were randomized into control or aprotinin groups. Patients in the aprotinin group received 280 mg of aprotinin in the pump prime. Plasma levels of soluble adhesion molecules were analyzed perioperatively. RESULTS: There were no significant changes in plasma sE-selectin after the operation in either group. Plasma sP-selectin increased significantly up to 20 h after reperfusion to the myocardium. Plasma sICAM-1 decreased in the early stage after cardiopulmonary bypass (CPB), then recovered at 4 h after reperfusion and a significant increase in sICAM-1 was observed 20 h later. There were no significant differences between the groups in postoperative changes in sP-selectin (p = 0.21) and sICAM-1 (p = 0.91). CONCLUSION: Pump prime aprotinin did not influence plasma levels of E-selectin, P-selectin and ICAM-1 in the present patients. The present results do not support the concept of an anti-inflammatory effect of pump prime aprotinin.     

Soluble Adhesion Molecules in Coronary Surgery and Cardiopulmonary Bypass with Pump Prime Aprotinin

Objective : The purpose of the present study was to establish whether pump prime aprotinin could influence soluble adhesion molecules in patients undergoing elective coronary artery bypass surgery. Design : Thirty patients admitted for first-time elective coronary artery bypass surgery were randomized into control or aprotinin groups. Patients in the aprotinin group received 280 mg of aprotinin in the pump prime. Plasma levels of soluble adhesion molecules were analyzed perioperatively. Results : There were no significant changes in plasma sE-selectin after the operation in either group. Plasma sP-selectin increased significantly up to 20 h after reperfusion to the myocardium. Plasma sICAM-1 decreased in the early stage after cardiopulmonary bypass (CPB), then recovered at 4 h after reperfusion and a significant increase in sICAM-1 was observed 20 h later. There were no significant differences between the groups in postoperative changes in sP-selectin ( p = 0.21) and sICAM-1 ( p = 0.91). Conclusion : Pump prime aprotinin did not influence plasma levels of E-selectin, P-selectin and ICAM-1 in the present patients. The present results do not support the concept of an anti-inflammatory effect of pump prime aprotinin.